HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients

F. Cappuzzo; L. Toschi; I. Domenichini; S. Bartolini; G. L. Ceresoli; E. Rossi; V. Ludovini; A. Cancellieri; E. Magrini; L. Bemis; W. A. Franklin; L. Crino; P. A. Bunn; F. R. Hirsch; M. Varella-Garcia

doi:10.1038/sj.bjc.6602865

HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients

F. Cappuzzo, L. Toschi, I. Domenichini, S. Bartolini, G. L. Ceresoli, E. Rossi, V. Ludovini, A. Cancellieri, E. Magrini, L. Bemis, W. A. Franklin, L. Crino, P. A. Bunn, F. R. Hirsch, M. Varella-Garcia

Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

Abstract

In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH + pattern was significantly associated with female gender (P = 0.02) and never smoking history (P = 0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P = 0.04) than patients with HER3-tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P = 0.03) and time to progression (7.7 vs 2.7 months, P = 0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3-tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.

Original language	English (US)
Pages (from-to)	1334-1340
Number of pages	7
Journal	British Journal of Cancer
Volume	93
Issue number	12
DOIs	https://doi.org/10.1038/sj.bjc.6602865
State	Published - Dec 12 2005

Bibliographical note

Funding Information:
We are indebted to the Department of Pathology of the Bellaria Hospital-Bologna, Institute San Raffaele-Milano and Policlinico Monteluce-Perugia for providing patient tissues and clinical data, to AstraZeneca for providing the drug for treatment, and to the Cytogenetics and Tissue Procurement Cores of the University of Colorado Cancer Center for technical assistance. NCI grants Cancer Center Core Grant 2P30-CA46934, Specialised Program of Research Excellence P01-CA58187. FC was a Visiting Professor at the University of Colorado Health Sciences Center sponsored in part by the Department of Medical Oncology of the Bellaria Hospital, Bologna, Italy and in part by the Associazione Italiana Ricerca sul Cancro (AIRC) grant number 2881.

Keywords

EGFR
Gefitinib
HER3
Non-small-cell lung cancer
Tyrosine kinase inhibitor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/sj.bjc.6602865

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Cappuzzo, F., Toschi, L., Domenichini, I., Bartolini, S., Ceresoli, G. L., Rossi, E., Ludovini, V., Cancellieri, A., Magrini, E., Bemis, L., Franklin, W. A., Crino, L., Bunn, P. A., Hirsch, F. R., & Varella-Garcia, M. (2005). HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients. British Journal of Cancer, 93(12), 1334-1340. https://doi.org/10.1038/sj.bjc.6602865

Cappuzzo, F, Toschi, L, Domenichini, I, Bartolini, S, Ceresoli, GL, Rossi, E, Ludovini, V, Cancellieri, A, Magrini, E, Bemis, L, Franklin, WA, Crino, L, Bunn, PA, Hirsch, FR & Varella-Garcia, M 2005, 'HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients', British Journal of Cancer, vol. 93, no. 12, pp. 1334-1340. https://doi.org/10.1038/sj.bjc.6602865

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abstract = "In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH + pattern was significantly associated with female gender (P = 0.02) and never smoking history (P = 0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P = 0.04) than patients with HER3-tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P = 0.03) and time to progression (7.7 vs 2.7 months, P = 0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3-tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.",

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author = "F. Cappuzzo and L. Toschi and I. Domenichini and S. Bartolini and Ceresoli, {G. L.} and E. Rossi and V. Ludovini and A. Cancellieri and E. Magrini and L. Bemis and Franklin, {W. A.} and L. Crino and Bunn, {P. A.} and Hirsch, {F. R.} and M. Varella-Garcia",

note = "Funding Information: We are indebted to the Department of Pathology of the Bellaria Hospital-Bologna, Institute San Raffaele-Milano and Policlinico Monteluce-Perugia for providing patient tissues and clinical data, to AstraZeneca for providing the drug for treatment, and to the Cytogenetics and Tissue Procurement Cores of the University of Colorado Cancer Center for technical assistance. NCI grants Cancer Center Core Grant 2P30-CA46934, Specialised Program of Research Excellence P01-CA58187. FC was a Visiting Professor at the University of Colorado Health Sciences Center sponsored in part by the Department of Medical Oncology of the Bellaria Hospital, Bologna, Italy and in part by the Associazione Italiana Ricerca sul Cancro (AIRC) grant number 2881.",

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doi = "10.1038/sj.bjc.6602865",

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T1 - HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients

AU - Cappuzzo, F.

AU - Toschi, L.

AU - Domenichini, I.

AU - Bartolini, S.

AU - Ceresoli, G. L.

AU - Rossi, E.

AU - Ludovini, V.

AU - Cancellieri, A.

AU - Magrini, E.

AU - Bemis, L.

AU - Franklin, W. A.

AU - Crino, L.

AU - Bunn, P. A.

AU - Hirsch, F. R.

AU - Varella-Garcia, M.

N1 - Funding Information: We are indebted to the Department of Pathology of the Bellaria Hospital-Bologna, Institute San Raffaele-Milano and Policlinico Monteluce-Perugia for providing patient tissues and clinical data, to AstraZeneca for providing the drug for treatment, and to the Cytogenetics and Tissue Procurement Cores of the University of Colorado Cancer Center for technical assistance. NCI grants Cancer Center Core Grant 2P30-CA46934, Specialised Program of Research Excellence P01-CA58187. FC was a Visiting Professor at the University of Colorado Health Sciences Center sponsored in part by the Department of Medical Oncology of the Bellaria Hospital, Bologna, Italy and in part by the Associazione Italiana Ricerca sul Cancro (AIRC) grant number 2881.

PY - 2005/12/12

Y1 - 2005/12/12

N2 - In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH + pattern was significantly associated with female gender (P = 0.02) and never smoking history (P = 0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P = 0.04) than patients with HER3-tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P = 0.03) and time to progression (7.7 vs 2.7 months, P = 0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3-tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.

AB - In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH + pattern was significantly associated with female gender (P = 0.02) and never smoking history (P = 0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P = 0.04) than patients with HER3-tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P = 0.03) and time to progression (7.7 vs 2.7 months, P = 0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3-tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.

KW - EGFR

KW - Gefitinib

KW - HER3

KW - Non-small-cell lung cancer

KW - Tyrosine kinase inhibitor

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HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients

Abstract

Bibliographical note

Keywords

UN SDGs

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